JP2017037048A - Chromatography separation method and chromatography separation system - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a chromatography separation method capable of separating and refining a refinement object component with high purity, at high density and at a high collection ratio.SOLUTION: A pseudo movement layer type chromatography separation method repeats steps (a)-(b) in the order: (a) a step for executing following sub steps (i)-(iv): (i) a step for supplying a liquid concentrate from a liquid concentrate supply hole F and extracting a high adsorptive fraction from a high adsorptive fraction extraction hole C; (ii) a step for supplying the liquid concentrate from the liquid concentrate supply hole F and extracting a low adsorptive fraction from a low adsorptive fraction extraction hole A; (iii) a step for supplying an eluent from an eluent supply hole D and extracting the low adsorptive fraction from the low adsorptive fraction extraction hole A; and (iv) a step for circulating a liquid in a circulation system without supplying the liquid concentrate and the eluent, and without extracting the high adsorptive fraction and the low adsorptive fraction; and (b) a step for shifting the liquid concentrate supply hole F, the low adsorptive fraction extraction hole A, the eluent supply hole D and the high adsorptive fraction extraction hole C in a flowing direction of the liquid while maintaining a relative positional relationship of them.SELECTED DRAWING: None

Description

  The present invention relates to a chromatographic separation method and a chromatographic separation system. More specifically, the present invention relates to a chromatographic separation method and chromatographic separation system using a pseudo moving bed system.

  The chromatographic separation methods are roughly classified into a fixed bed method and a moving bed method. In the fixed bed system, a multi-component sample (hereinafter also referred to as “stock solution”) is injected into a column filled with an adsorbent, and the eluent is circulated in one direction in the column, thereby allowing the adsorbent to be adsorbed. The target component in the stock solution is separated and purified from other components based on the difference in adsorption power. In this fixed bed system, the target component can be separated and purified simply by circulating the eluent while fixing the adsorbent. However, if there is no significant difference in the adsorptive power with respect to the adsorbent between the target component to be purified (hereinafter, also simply referred to as “component to be purified”) and other components, the fixed layer method is good. Separation and purification cannot be realized. Furthermore, in the fixed layer method, the target component cannot be separated while continuously injecting the sample, and there are limitations in industrial application.

On the other hand, in the moving bed method, the adsorbent is moved in the opposite direction to the flow direction of the eluent while flowing the eluent in one direction in the column. In the moving bed method, by adjusting the flow rate of the eluent and the moving speed of the adsorbent, the component to be purified in the stock solution is moved in the direction opposite to the direction of other components, based on the stock solution inlet. Can be made. Therefore, for example, when the component to be purified in the stock solution is a strongly adsorbing component compared to other components, the component to be purified is upstream with respect to the inlet of the stock solution (the direction opposite to the fluid flow direction). Therefore, it is possible to construct a system in which other components move downstream (fluid flow direction). By extracting the component to be purified on the upstream side and extracting other components on the downstream side, the component to be purified can be separated and purified continuously and with higher purity while continuously injecting the stock solution.
However, industrial application of the moving bed method is not easy. In a chromatographic separation system using a large column used industrially, it is technically difficult to move the adsorbent uniformly. Even if the adsorbent can be moved uniformly, a large load is applied to the adsorbent during this movement. As a result, the adsorbent easily breaks (crushes), and the constructed chromatographic separation system tends to be inferior in practicality in terms of durability.

  In order to solve the problems of the moving bed system, a chromatographic separation technique using a pseudo moving bed system has been proposed (for example, Patent Documents 1 and 2). The chromatographic separation by the simulated moving bed system is performed using a circulation system in which a plurality of unit packed columns (columns) packed with an adsorbent are connected in series and endlessly through a pipe. In this circulation system, the pipe has a stock solution supply port for supplying a stock solution containing the component to be purified, a weak adsorbent component outlet, an eluent supply port, and a strong adsorbent component outlet for fluid flow. And in this order, and between the stock solution supply port and the weak adsorbent component outlet, between the weak adsorbent component outlet and the eluent supply port, and between the eluent supply port and the strong adsorbent component. At least one of the above unit packed towers is disposed between the outlet and between the strongly adsorbing component outlet and the stock solution supply port. The stock solution supply port, the weakly adsorbent component outlet, the eluent supply port, and the strong adsorbent component outlet are intermittently directed toward the fluid flow direction while maintaining their relative positional relationship. By moving the adsorbent, it is possible to obtain the same effect as when the adsorbent is moved in the direction opposite to the fluid flow direction even though the adsorbent is fixed.

Japanese Patent Publication No. 60-55162 JP 2009-36536 A

In chromatographic separation, in addition to the stock solution containing the component to be purified, an eluent that pushes the stock solution is supplied. Therefore, the target fraction containing the component to be purified (hereinafter also referred to as “fraction to be purified”) is in a state in which the component to be purified is diluted to some extent with the eluent. Therefore, although the fraction to be purified obtained by chromatographic separation is usually shipped through a concentration operation, this concentration operation contributes to increase the purification cost.
In order to reduce such costs, it is necessary to increase the concentration of the component to be purified in the fraction to be purified. However, if the amount of eluent used in chromatographic separation is reduced in order to increase the concentration of the purification target component, the separation performance generally decreases, and the purity of the purification target component in the resulting purification target fraction (in the purification target fraction, And the ratio of the component to be purified in the remainder excluding the solvent in the stock solution). Furthermore, when the amount of the eluent used is reduced, the recovery rate of the purification target component contained in the stock solution into the purification target fraction also tends to decrease.

The present invention is a chromatographic separation method using a simulated moving bed system, which can greatly reduce the amount of eluent used, and also provides the recovery rate of the purification target component in the obtained purification target fraction, and the purification target It is an object of the present invention to provide a chromatographic separation method capable of highly enhancing any of the purities of the components to be purified in the fraction.
Moreover, this invention makes it a subject to provide the chromatographic separation system suitable for implementation of the said chromatographic separation method.

As a result of intensive studies in view of the above problems, the inventors of the present invention have found that in a chromatographic separation method using a simulated moving bed system, a liquid supply operation selected from a stock solution supply operation and an eluent supply operation, and a strong adsorptive fraction extraction A process of performing a specific combination of a liquid extraction operation selected from a discharge operation and a weakly adsorptive fraction extraction operation in a specific order, and a fluid in the system without performing any liquid supply operation or liquid extraction operation. In combination with a circulation process that circulates, the amount of eluent used can be greatly reduced, while the purity of the purification target component in the purification target fraction and the recovery rate of the purification target component in the purification target fraction can be reduced. It has been found that both can be raised to a desired level. That is, it has been found that the components to be purified can be separated and purified at a high concentration, high purity, and high recovery rate in the fraction to be purified.
The present invention has been further studied based on these findings and has been completed.

The above-described problems of the present invention have been solved by the following means.
[1]
A chromatographic separation method for separating and purifying components in a stock solution by a simulated moving bed method using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly through a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
The following steps (a) and (b) are repeated in order:
(A) performing the following substeps (i) to (iv) in this order;
(I) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the strong adsorptive fraction from the strong adsorptive fraction extraction outlet C;
(Ii) a sub-step of supplying a stock solution from the stock solution supply port F and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(B) After the step (a) is completed, the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.
[2]
The chromatographic separation method according to [1], wherein in the step (a), the total amount of the strongly adsorptive fraction extracted from the outlet C is smaller than the total amount of the stock solution supplied from the supply port F. .
[3]
The chromatographic separation method according to [1] or [2], wherein the stock solution contains glucose and fructose, and the fructose is separated and purified in the strong adsorptive fraction.
[4]
The chromatographic separation method according to any one of [1] to [3], wherein the circulation system has at least four unit packed columns.
[5]
In the step (a), the ratio of the total supply amount of the eluent to the total supply amount of the stock solution satisfies the ratio [total supply amount of eluent] / [total supply amount of stock solution] <1.2 in volume ratio. The chromatographic separation method according to any one of [1] to [4].
[6]
A chromatographic separation system that separates and purifies components in a stock solution by a simulated moving bed system using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
Repeat the following steps (a) and (b) in order, system:
(A) performing the following substeps (i) to (iv) in this order;
(I) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the strong adsorptive fraction from the strong adsorptive fraction extraction outlet C;
(Ii) a sub-step of supplying a stock solution from the stock solution supply port F and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(B) After the step (a) is completed, the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.

In this specification, the terms “upstream” and “downstream” are used with respect to the flow direction of the fluid in the circulation system. That is, the “upstream side” with respect to a certain part of the circulatory system means the side where the fluid flows toward the part, and the “downstream side” means the side where the fluid flows out from the part. means.
In the present specification, “strongly adsorbing component” means a component having a strong adsorptive power to the adsorbent among a plurality of components contained in the stock solution, and “weakly adsorbing component” means the above strongly adsorbing component. Means a component having a lower adsorptivity to the adsorbent. In other words, the terms “strongly adsorbing” and “weakly adsorbing” represent the degree of strength of the adsorbing force when the adsorbing force relative to the adsorbent is relatively compared for each component contained in the stock solution. Is.
Further, each of the “strongly adsorbing component” and the “weakly adsorbing component” may be composed of a single component or a plurality of components having different adsorptive powers. Since the component to be purified is often a single component, when the strongly adsorbing component is the component to be purified, the strongly adsorbing component is usually the component having the strongest adsorption power to the adsorbent in the stock solution. However, the present invention is not limited to this embodiment. The weakly adsorptive component is one or more components that are less adsorbable to the adsorbent than the strong adsorbent component. Similarly, when the weakly adsorptive component is a component to be purified, the weakly adsorbable component is usually the component having the weakest adsorption power to the adsorbent in the stock solution, but the present invention is limited to this embodiment. It is not a thing. The strong adsorptive component is one or more components having a higher adsorptivity to the adsorbent than the weak adsorptive component.

  According to the chromatographic separation method of the present invention, the components to be purified in the stock solution can be separated and purified at a high concentration, a high purity, and a high recovery rate. The chromatographic separation system of the present invention can be used for carrying out the chromatographic separation method of the present invention.

FIG. 1 is a system diagram showing an embodiment of the chromatographic separation system of the present invention. FIG. 2 is an explanatory diagram for explaining the basic concept of chromatographic separation by the pseudo moving bed method.

  A preferred embodiment of the chromatographic separation method of the present invention (hereinafter also simply referred to as “the method of the present invention”) will be described.

The method of the present invention is carried out using a circulation system in which a plurality of unit packed towers filled with an adsorbent are connected in series and endlessly through a pipe. The circulation system itself used in the simulated moving bed system is known, and for example, JP 2009-36536 A and JP 7-46097 A can be referred to.
The circulatory system will be described below with reference to the drawings, but the present invention is not limited to these embodiments.
The drawings referred to below are explanatory diagrams for facilitating the understanding of the present invention, and the size and relative size relationship of each component may be changed for convenience of explanation, and the actual relationship may be changed. It is not shown as it is. Further, the present invention is not limited to the shapes and relative positional relationships shown in these drawings except for the matters defined in the present invention.

A preferred embodiment of the circulatory system used in the method of the present invention is shown in FIG. The circulation system 100 shown in FIG. 1 includes four unit packed columns (unit packed columns 10a, 10b, 10c, and 10d) packed with an adsorbent Ab, and the outlet of each unit packed column is an adjacent unit packed column. The unit packed towers are connected in series as a whole.
The outlet of the last unit packed column (for example, the unit packed column 10d) is connected to the inlet of the frontmost unit packed column (for example, the unit packed column 10a) via the pipe 1, and all the unit packed columns are endless. Connected in a circular shape. With this configuration, the fluid can be circulated in the circulation system 100. It is preferable that the unit packed towers 10a to 10d have the same internal shape, size, and adsorbent filling amount (preferably the same).

  In the circulation system 100, a circulation pump P1 for circulating fluid in the direction of the arrow is disposed. The circulation pump P1 is preferably a metering pump. Further, in the circulation system 100, the piping 1 between two adjacent unit packed towers is provided with shutoff valves R1, R2, R3, and R4 that can block the flow of fluid to the downstream unit packed tower. It has been.

  Between each shutoff valve R1-R4 and the outlet of each unit packed tower 10a-10d located on the upstream side thereof, a fraction containing a large amount of weakly adsorptive components for the adsorbent Ab (in this specification, “ The weakly adsorbable fraction extraction lines 2a, 2b, 2c, and 2d for extracting the “weakly adsorbable fraction with respect to the adsorbent Ab” or simply “the weakly adsorbable fraction”) are branched. Each weakly adsorptive fraction extraction line 2a, 2b, 2c, 2d has a weakly adsorptive fraction extraction valve A1, A2, A3, A4 that can open and close each weakly adsorptive fraction extraction line. Is provided. Each weakly adsorptive fraction extraction line 2a, 2b, 2c, 2d is merged and combined into one weakly adsorptive fraction confluence tube 3.

  Similarly, a fraction containing a large amount of strongly adsorbing components for the adsorbent Ab between the shutoff valves R1 to R4 and the outlets of the unit packed towers 10a to 10d located on the upstream side thereof (this specification) In FIG. 4, the strong adsorptive fraction extraction lines 4a, 4b, 4c, and 4d for extracting “the strongly adsorbable fraction with respect to the adsorbent Ab” or simply “the strong adsorptive fraction”) are branched. The strong adsorptive fraction extraction lines 4a, 4b, 4c, and 4d have strong adsorptive fraction extraction valves C1, C2, C3, and C4 that can open and close the strong adsorptive fraction extraction lines, respectively. Is provided. The strong adsorptive fraction extraction lines 4 a, 4 b, 4 c, and 4 d are joined together and combined into one strong adsorptive fraction confluence pipe 5.

  In step (a) to be described later, one of the weakly adsorbing fraction extraction valves A1, A2, A3, and A4 is opened. A connection site between the weakly adsorptive fraction extraction line in which the opened extraction valve is installed and the pipe 1 serves as the weakly adsorptive fraction outlet A in the step (a). In step (a), one of the strong adsorptive fraction extraction valves C1, C2, C3, and C4 is opened. The connection site between the strongly adsorbable fraction extraction line where the opened extraction valve is installed and the pipe 1 becomes the outlet C of the strong adsorptive fraction in step (a).

  In order to prevent the pressure of the circulation system 100 from rising excessively, the circulation system 100 is preferably provided with a safety valve (or a relief valve) that is not shown in an appropriate portion. It is also preferable to provide check valves T1, T2, T3, and T4 for preventing backflow between two adjacent unit packed columns.

As shown in FIG. 1, the circulation system 100 is configured to be able to supply the stock solution 7 stored in the stock solution tank 6 and the eluent 9 stored in the eluent tank 8. The stock solution 7 is supplied via the stock solution supply line 11 by a stock solution supply pump P2 capable of controlling the supply flow rate. The stock solution supply pump P2 is preferably a metering pump. The stock solution supply line 11 preferably includes a relief valve U that returns the stock solution to the stock solution tank 6 when the supply pressure exceeds a set pressure during the supply of the stock solution. As shown in FIG. 1, the stock solution supply line 11 is branched into four stock solution supply branch lines 11a, 11b, 11c, and 11d, and the stock solution is supplied through each of the stock solution supply branch lines 11a, 11b, 11c, and 11d. The unit can be supplied to the entrances of the unit packed towers 10a, 10b, 10c, and 10d. Each stock solution supply branch line 11a, 11b, 11c, 11d is provided with an openable / closable stock solution supply valve F1, F2, F3, F4, through the stock solution supply branch line having the opened stock solution supply valve, The stock solution is supplied to the unit packed tower connected downstream.
In step (a), which will be described later, one of the stock solution supply valves F1, F2, F3, and F4 is opened. The connection site between the undiluted solution supply branch line where the unfolded undiluted solution supply valve is installed and the pipe 1 becomes the undiluted solution supply port F in step (a).

The eluent 9 is supplied via an eluent supply line 12 by an eluent supply pump P3 capable of controlling the supply flow rate. The eluent supply pump P3 is preferably a metering pump. The eluent supply line 12 preferably includes a relief valve V that returns the eluent to the eluent tank 8 when the supply pressure exceeds a set pressure during the supply of the eluent. As shown in FIG. 1, the eluent supply line 12 is branched into four eluent supply branch lines 12a, 12b, 12c, and 12d, and the eluent supply line 12a, 12b, 12c, and 12d are eluted. The liquid can be supplied to the entrances of the unit packed towers 10a, 10b, 10c, and 10d. Each eluent supply branch line 12a, 12b, 12c, 12d is provided with an eluent supply valve D1, D2, D3, D4 that can be opened and closed, and an eluent supply branch line having an opened eluent supply valve. Then, the eluent is supplied to the unit packed column connected downstream thereof.
In step (a) described later, any one of the eluent supply valves D1, D2, D3, and D4 is opened. A connecting portion between the eluent supply branch line where the opened eluent supply valve is installed and the pipe 1 becomes the eluent supply port D in step (a).

  Subsequently, the operation of the circulation system when the method of the present invention is performed by the circulation system will be described. In the method of the present invention, the following steps (a) and (b) are repeated in order using the circulation system.

(A) A step of performing the following sub-steps (i) to (iv) in this order.
(I) A sub-step of supplying the stock solution from the stock solution supply port F and extracting the strong adsorptive fraction from the strong adsorptive fraction outlet C.
(Ii) A sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A.
(Iii) A sub-step of supplying the eluent from the eluent supply port D and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A.
(Iv) A sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.
(B) After completion of the step (a) (that is, after completion of the sub-step (iv)), the stock solution supply port F, the weakly adsorbable fraction extraction port A, the eluent supply port D, and the strong adsorption The step of moving the sex fraction extraction outlet C toward the fluid flow direction while maintaining the relative positional relationship thereof.

[Step (a)]
The step (a) is a step of sequentially executing the four sub-steps (i) to (iv). Each sub-step will be described with reference to the circulation system shown in FIG.

<Substep (i)>
In substep (i), the strong adsorptive fraction is extracted from the strong adsorptive fraction extraction outlet C while supplying the stock solution from the stock solution supply port F. For example, when the stock solution supply valve F1 is opened and the stock solution supply pump P2 is operated to connect the stock solution supply branch line 11a and the pipe 1 to the stock solution supply port F, the extraction valve C3 is opened, A connecting portion between the strong adsorptive fraction extraction line 4c and the pipe 1 is defined as an outlet C.

  In substep (i), the stock solution supply valves F2 to F4, the weakly adsorptive fraction extraction valves A1 to A4, the strong adsorptive fraction extraction valves C1, C2 and C4, and the shutoff valve R3 are all closed. The eluent supply valves D1 to D4 may be opened as long as the eluent supply pump P3 is stopped. However, in order to perform the supply and extraction of the liquid with higher accuracy, the eluent supply valve The valves D1 to D4 are preferably closed. The shutoff valves R1 and R2 are open, and the shutoff valve R4 may be open or closed. The circulation pump P1 and the eluent supply pump P3 are normally stopped.

  In substep (i), the amount of the stock solution supplied from the stock solution supply port F is not particularly limited, but is 0.032 per liter of the adsorbent Ab packed in the unit packed column 10a per hour. It is preferable to set it as -0.059 liter, and it is more preferable to set it as 0.036-0.054 liter. The total supply amount of the stock solution in the sub-step (i) is substantially the same as the total amount of the strong adsorptive fraction extracted from the strong adsorptive fraction extraction outlet C in the sub-step (i).

<Sub-step (ii)>
In substep (ii), the weakly adsorptive fraction is extracted from the weakly adsorbable fraction outlet A while supplying the stock solution from the stock solution supply port F. That is, the strong adsorptive fraction extraction valve C3 that has been opened in the substep (i) is closed, and the weak adsorptive fraction extraction valve A1 is opened instead. That is, the connection part of the weakly adsorptive fraction extraction line 2a having the weakly adsorptive fraction extraction valve A1 and the pipe 1 is defined as the weakly adsorptive fraction extraction outlet A, and the weakly adsorptive fraction is extracted from the outlet A. Extract.

  In sub-step (ii), the stock solution supply valves F2 to F4, the weakly adsorbing fraction extraction valves A2 to A4, the strong adsorbing fraction extraction valves C1 to C4, and the shutoff valve R1 are all closed. The eluent supply valves D1 to D4 may be opened as long as the eluent supply pump P3 is stopped. However, in order to perform the supply and extraction of the liquid with higher accuracy, the eluent supply valve The valves D1 to D4 are preferably closed. The shutoff valves R2-4 may be open or closed. Further, as in the substep (i), the circulation pump P1 and the eluent supply pump P3 are normally stopped.

  In substep (ii), the amount of the stock solution supplied from the stock solution supply port F is not particularly limited, but is 0.020 to 1 hour per liter of the adsorbent Ab packed in the unit packed column 10a per hour. It is preferable to set it as 0.036 liter, and it is more preferable to set it as 0.022-0.034 liter. The total supply amount of the stock solution in the sub-step (ii) is substantially the same as the total amount of the weakly adsorbable fraction extracted from the weakly adsorbable fraction outlet A in the substep (ii).

<Sub-step (iii)>
In substep (iii), the eluent is supplied from the eluent supply port D and the weakly adsorbable fraction is extracted from the weakly adsorbable fraction outlet A. That is, the supply valve F1 opened in the substep (ii) is closed, the operation of the stock solution supply pump P2 is stopped, and the eluent supply valve D3 is opened instead, and the eluent supply pump P3 is operated. That is, the connection part of the eluent supply branch line 12c having the supply valve D3 and the pipe 1 serves as the eluent supply port D, and the eluent is supplied from the eluent supply port D and the weakly adsorbing fraction. A weakly adsorptive fraction is extracted from the outlet A.

  In sub-step (iii), the eluent supply valves D1, D2 and D4, the weakly adsorbing fraction extraction valves A2 to A4, the strong adsorbing fraction extraction valves C1 to C4 and the shutoff valve R1 are all closed. ing. The stock solution supply valves F1 to F4 may be opened as long as the stock solution supply pump P2 is stopped. However, in order to perform the supply and extraction of the solution with higher accuracy, the stock solution supply valves F1 to F4 are It is preferably closed. The shutoff valve R2 may be open or closed. The shutoff valves R3 and R4 are both open. Further, the circulation pump P1 may be operated or stopped.

  In the sub-step (iii), the amount of the eluent supplied from the eluent supply port D is not particularly limited, but is 0. 1 per liter of the adsorbent Ab packed in the unit packed column 10a per hour. It is preferable to set it as 051-0.095 liter, and it is more preferable to set it as 0.058-0.088 liter. The total supply amount of the eluent in the sub-step (iii) is substantially the same as the total amount of the weakly adsorptive fraction extracted from the weakly adsorptive fraction outlet A in the substep (iii).

<Sub-step (iv)>
In sub-step (iv), the supply of the stock solution and the eluent is not performed, and the fluid in the circulation system is operated by operating the circulation pump P1 without extracting the strong and weakly adsorbable fractions. Simply circulate. As long as the stock solution supply pump P2 and the eluent supply pump P3 are stopped, the stock solution supply valves F1 to F4 and the eluate supply valves D1 to D4 may be opened, but from the viewpoint of controlling the fluid with higher accuracy, The stock solution supply valves F1 to F4 and the eluent supply valves D1 to D4 are preferably closed. The extraction valves A1 to A4 and the extraction valves C1 to C4 are all closed, and the shutoff valves R1 to R4 are all open.

  In substep (iv), the circulation flow rate of the fluid in the system is preferably 0.133 to 0.247 liters per liter of the adsorbent Ab packed in the unit packed column 10a per hour, More preferably, it is 0.152 to 0.228 liter.

  The relationship between the supply amount of liquid and the circulation flow rate in each sub-step is not particularly limited, and can be appropriately adjusted according to the type of components in the stock solution. Usually, the total amount (I) of the stock solution supplied from the stock solution supply port F in the substep (i) and the total amount (II) of the stock solution supplied from the stock solution supply port F in the substep (ii). Is a volume ratio, and the total amount (II) / total amount (I) is preferably 0.30 to 0.70, and more preferably 0.40 to 0.60.

  Further, the total amount (I) of the stock solution supplied from the stock solution supply port F in the substep (i), and the total amount of the eluent supplied from the eluent supply port D (the substep (iii)) ( The relationship with III) is, by volume ratio, preferably the total amount (III) / total amount (I) = 1.14 to 2.11, and more preferably 1.30 to 1.95.

  Further, the total amount (I) of the stock solution supplied from the stock solution supply port F in the substep (i), and the total amount (II) of the stock solution supplied from the stock solution supply port F in the substep (ii). And the total amount (III) of the eluent supplied from the eluent supply port D in the sub-step (iii) in the volume ratio, the total amount (III) / total amount (I + II) = 0.5 to 1.5 is preferable, and 0.7 to 1.2 is more preferable.

  Further, in the substep (i), the relationship between the total amount (I) of the stock solution supplied from the stock solution supply port F and the total circulation flow rate in the substep (iv) is the volume ratio, and the total circulation flow rate / Total amount (I) = 3.0 to 5.0 is preferable, and 3.5 to 4.5 is more preferable.

In the circulation system used in the present invention, the amount of adsorbent packed in one unit packed column is not particularly limited and may be appropriately selected according to the purpose, but is usually 10 mL to 150 m ³ , preferably Is 150 mL to ³⁰ m ³ , more preferably 300 mL to 15 m ³ .
In addition, the relationship between the total capacity of the adsorbent Ab filled in all the unit packed towers in the circulation system and the total volume of the pipe 1 (the total volume in the cavity of the pipe 1) is a volume ratio [pipe 1 Of the total volume] / [total capacity of the adsorbent Ab] = 0.01 to 0.2.

  The ratio of the total supply amount of the eluent to the total supply amount of the stock solution in the above step (a) (ie in the above substeps (i) to (iv)) (corresponding to the above total amount (III) / total amount (I + II)) Is more preferable to satisfy [total supply amount of eluent] / [total supply amount of stock solution] <1.2, and [total supply amount of eluent] / [total supply amount of stock solution] ≦ 1.1. It is more preferable to satisfy. The lower limit of the ratio is not particularly limited, and it is more practical to set [total amount of eluent supplied] / [total amount of stock solution] ≧ 0.5. The ratio is more preferably 0.5 ≦ [total supply amount of eluent] / [total supply amount of stock solution] ≦ 1.1, and 0.8 ≦ [total supply amount of eluent] / [total amount of stock solution]. It is also preferable that the total supply amount] ≦ 1.1.

The temperature for carrying out the method of the present invention is not particularly limited as long as the fluid in the circulation system is liquid, and is appropriately selected according to the purpose. Usually, it is carried out at 40 to 80 ° C.
In the method of the present invention, the flow rate of the supplied liquid or the flow rate of the liquid circulating in the circulation system may be constant during each sub-step or may be varied, but is usually constant. . Further, between each sub-step, the flow rate of the supplied liquid or the flow rate of the liquid circulating in the circulation system may be constant or may be varied, but is usually constant. That is, in substeps (i) to (iii), the flow rate of the supplied liquid is preferably constant. In substep (iv), the flow rate of the liquid circulating in the circulation system is also the same as that in substeps (i) to (i). The flow rate of the liquid supplied in (iii) is preferably the same.

[Step (b)]
After the step (a) is completed (after the completion of the sub-step (iv)), the step (b) is performed. In the step (b), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D and the strong adsorptive fraction extraction port C are maintained in their relative positional relationship. This is a step of moving the fluid in the direction of fluid flow.
In this specification, “the flow direction of the fluid while maintaining the relative positional relationship between the stock solution supply port F, the weakly adsorbable fraction outlet A, the eluent supply port D, and the strong adsorptive fraction outlet C”. "Migrate toward the end" means that the stock solution supply port F, the weakly adsorbable fraction extraction port A, the eluent supply port D, and the strong adsorptivity that were arranged in order in the fluid flow direction in the immediately preceding step (a). This means that the order of the fraction extraction outlets C is switched between the strong adsorptive fraction extraction outlet C, the stock solution supply port F, the weak adsorptive fraction extraction port A, and the eluent supply port D, respectively.
In other words, with the positions of all the unit packed columns fixed, the positions of the stock solution supply port F, the weakly adsorbable fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction outlet C are set. By switching
1) A unit packed tower between the stock solution supply port F and the weakly adsorbable fraction extraction outlet A in the immediately preceding step (a) is placed between the strong adsorptive fraction extraction port C and the stock solution supply port F.
2) A unit packed tower between the weakly adsorbing fraction extraction outlet A and the eluent supply port D in the immediately preceding step (a) is placed between the stock solution supply port F and the weakly adsorbing fraction extraction outlet A.
3) The unit packed tower between the eluent supply port D and the strong adsorptive fraction extraction outlet C in the immediately preceding step (a) is placed between the weak adsorbent fraction extraction outlet A and the eluent supply port D. ,
4) The unit packed tower between the strong adsorptive fraction extraction outlet C and the stock solution supply port F in the immediately preceding step (a) is arranged between the eluent supply port D and the strong adsorptive fraction extraction port C, respectively. It means to be placed.
In the form of the circulatory system in FIG. 1, this step (b) is not a step for giving a physical change to the structure of the circulatory system, but a preparatory process for carrying out step (a) following this step (b). It is.

The step (b) will be specifically described with reference to FIG.
Assume that in step (a) immediately before step (b), the supply valve F1 is opened to supply the stock solution. In this case, in step (a), the stock solution supply port F is connected to the stock solution supply branch line 11a and the pipe 1,
The weakly adsorptive fraction extraction outlet A is a connection site between the weakly adsorptive fraction extraction line 2a and the pipe 1,
The eluent supply port D is connected to the eluent supply branch line 12c and the pipe 1;
The strong adsorptive fraction extraction outlet C is a connecting portion between the strong adsorptive fraction extraction line 4 c and the pipe 1.
The ports F, A, D, and C in step (a) are switched as follows by step (b). That is,
The stock solution supply port F becomes a connection part between the stock solution supply branch line 11b and the pipe 1,
The weakly adsorptive fraction extraction outlet A is a connection site between the weakly adsorptive fraction extraction line 2b and the pipe 1,
The eluent supply port D becomes a connecting portion between the eluent supply branch line 12d and the pipe 1,
The strong adsorptive fraction extraction outlet C serves as a connection site between the strong adsorptive fraction extraction line 4 d and the pipe 1.
That is, in step (a) immediately after step (b), the supply of the stock solution in substeps (i) and (ii) is performed through the stock solution supply branch line 11b, and the eluent in substep (iii) is supplied. Supply is performed through the eluent supply branch line 12d, extraction of the strong adsorptive fraction in sub-step (i) is performed through the strongly adsorbent fraction extraction line 4d, and weak in sub-steps (ii) and (iii). Extraction of the adsorptive fraction is performed through the weakly adsorptive fraction extraction line 2b.

  By repeating the steps (a) and (b) in order, the method of the present invention by the pseudo movement method is implemented.

By repeating the above steps (a) and (b) in sequence, the amount of the eluent used can be greatly reduced compared to the chromatographic separation by the normal simulated moving bed method, and in the strong adsorptive fraction and weakly adsorbed. It is possible to effectively reduce the ratio of the eluent in the soluble fraction (that is, the concentration of components other than the eluent in the strongly adsorbable fraction and the weakly adsorbable fraction can be increased). In addition, the method of the present invention can also improve the separation performance between the component to be purified and other components. Therefore, when the component to be purified is a strong adsorptive component, the strong adsorbent component can be obtained with high purity and a high recovery rate in the strong adsorptive fraction, and the component to be purified is weakly adsorbed. In the case of an absorptive component, a weakly adsorbable component can be obtained with high purity and a high recovery rate in the weakly adsorbable fraction. That is, according to the method of the present invention, the target component to be purified can be obtained in a high concentration, a high purity, and a high recovery rate in a fraction selected from a strong adsorptive fraction and a weakly adsorptive fraction. .
In the method of the present invention, the component to be purified is preferably a strongly adsorptive component.

  Here, in the chromatographic separation by the simulated moving bed system, the general conditions of the supply and extraction of the liquid that should be satisfied in order to realize good separation and purification are shown in FIG. This will be described with reference to the drawings. FIG. 2 shows the section 1 between the eluent supply port D and the strong adsorbent component outlet C, the section 2 between the strong adsorbent component outlet C and the stock solution supply port F, and the stock solution supply port F and the weak adsorption. The section up to the sex component outlet A is shown as section 4. V1 to V4 mean the flow rates of sections 1 to 4 per cycle (until each port D, C, F, A is moved once). The arrows in FIG. 2 indicate the direction of fluid flow.

Focusing on Sections 2 and 3, in order to realize the pseudo moving bed system, the weakly adsorbing component moves beyond the length of Section 2 at the flow rate V2, and the movement of the strongly adsorbing component is the distance of Section 2. The weakly adsorbing component moves beyond the length of the section 3 at the flow rate V3, and the movement of the strong adsorbing component needs to be suppressed to less than the distance of the section 3. In this way, when these are moved downstream with respect to the positions of the respective ports D, C, F, A, the weakly adsorbing components are further moved downstream, and the strong adsorbing components are upstream. Can be moved relatively (pseudo). That is, the weakly adsorbable component can be extracted from the outlet A, and the strong adsorptive component can be extracted from the outlet C.
On the other hand, paying attention to section 1, if the moving distance of the strong adsorptive component is less than the length of section 1 at the flow rate V1, the strong adsorptive component (passes upstream without being extracted from the outlet C). The strongly adsorbing component that has been removed cannot be extracted from the outlet C. Therefore, in section 1, it is said that the moving distance of the strongly adsorbing component needs to move beyond the length of section 1 at flow rate V1.
Further, when attention is paid to section 4, when the moving distance of the weakly adsorbing component exceeds the length of section 4 at the flow rate V4, the weakly adsorbing component (weakly adsorbing that has passed without being extracted from the outlet A). Sex component) cannot be extracted from the outlet A. Therefore, in section 4, it is said that the moving distance of the weakly adsorbing component needs to be less than the length of section 4 at flow rate V4.

Focusing on the relationship between section 3 and section 1 above, it can be understood that the flow rate V3 and the flow rate V1 need to satisfy V3 <V1 (in the case of section 1, the strongly adsorbent component is moved farther). Need to be).
Here, since V3 = V2 + [feed amount of stock solution] and V1 = V2 + [extraction amount of strong adsorptive fraction],
V3 <V1 is V2 + [feed amount of stock solution] <V2 + [extraction amount of strong adsorptive fraction], that is, [feed amount of stock solution] <[extraction amount of strong adsorptive fraction].
Therefore, in the simulated moving bed type chromatographic separation, the supply amount of the stock solution is usually smaller than the extraction amount of the strong adsorptive fraction.

On the other hand, in the method of the present invention, it is preferable that the supply amount of the stock solution is made larger than the extraction amount of the strong adsorptive fraction. In step (a), by carrying out each of the sub-steps so that the supply amount of the stock solution is larger than the extraction amount of the strong adsorptive fraction, the component to be purified can be further contained in the fraction to be purified. High concentrations, higher purity, and higher recovery can be obtained.
In the method of the present invention, the ratio of the supply amount (total supply amount) of the stock solution in step (a) to the extraction amount (total extraction amount) of the strong adsorptive fraction in step (a) is a volume ratio, [Stock solution supply amount] / [Strong adsorbable fraction withdrawal amount] = 1.0 to 2.0 is preferred, [Stock solution feed amount] / [Strong adsorptive fraction withdrawal amount] = 1. 2-1.8 is more preferable.

The method of the present invention includes various modifications in addition to the embodiments specifically described above. For example, between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorptive fraction outlet A and the eluent supply port D, eluent supply port D and the strong adsorptive fraction outlet One unit packed tower may be provided between C and the strongly adsorbing fraction outlet C and the stock solution supply port F, or two or more units may be provided. May be. That is, the circulation system preferably has at least 4 unit packed towers, and more preferably has 4 unit packed towers.
In addition, substeps other than the substeps (i) to (iv) may be inserted in the step (a) for a short time as long as the effects of the present invention are not substantially impaired. Such forms are also encompassed by the method of the present invention. For example, when the adsorbent has deteriorated due to long-term use or the like, in substep (ii), the stock solution is supplied from the stock solution supply port F and the weakly adsorbable fraction is extracted from the weakly adsorbable fraction outlet A. In addition to the process (FA process), separation is improved by incorporating a process (DC process) for supplying the eluent from the eluent supply port D and extracting the strongly adsorbable fraction from the strong adsorbent fraction outlet C (DC process). Yes. When a DC process is incorporated in step (ii), it is preferable to perform the DC process simultaneously with the FA process in step (ii). However, from the viewpoint of effectively reducing the eluent, it is preferable to perform only the FA step in substep (ii).

In the method of the present invention, the adsorbent packed in the unit packed column is appropriately selected according to the component to be purified, and various adsorbents can be employed. For example, adsorb strong acid cation exchange resin, weak acid cation exchange resin, strong base anion exchange resin, weak base anion exchange resin, synthetic adsorbent, zeolite, and silica gel (preferably octadecylsilyl modified silica gel) It can be used as an agent.
Among these, the method of the present invention is a suitable method for separating and purifying a specific monosaccharide from a stock solution containing a plurality of monosaccharides using a strongly acidic cation exchange resin as an adsorbent. In particular, it is a suitable method for separating and purifying fructose from a stock solution containing glucose and fructose. The strongly acidic cation exchange resin is preferably in the calcium form, silver form, lead form, or strontium form, and more preferably in the calcium form in consideration of economy and safety. As this calcium type strong acid cation exchange resin, for example, Amberlite (registered trademark) CR-1310Ca, CR-1320Ca (both manufactured by Organo), DOWEX (registered trademark) Monosphere 99Ca / 310, Monosphere 99Ca / 320 ( Examples include all manufactured by Dow Chemical Co., Ltd., Diaion (registered trademark) UBK535, UBK555 (all manufactured by Mitsubishi Chemical), PCR642Ca (manufactured by Purolite), CS11GC, and CS16GC (all manufactured by Finex).

  The chromatographic separation system of the present invention is a system for carrying out the method of the present invention. That is, the chromatographic separation system of the present invention is a system having the above-described circulation system configuration, in which the circulation system sequentially repeats the operation of step (a) and the operation of step (b).

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to the following Example. In the following examples, “%” representing the component composition is based on mass unless otherwise specified.

[Preparation of stock solution]
53.49 parts by mass of glucose, 41.81 parts by mass of fructose and 4.70 parts by mass of oligosaccharide were dissolved in deionized water to prepare an aqueous solution having a total sugar concentration of 60%, which was used as a stock solution.

[Preparation of eluent]
Ion exchange water was used as an eluent.

[Chromatograph separation system]
By using the circulation system shown in FIG. 1, the fructose was separated and purified from the stock solution. As the unit packed towers 10a to 10d, cylindrical packed towers having an inner diameter of 22 mm and a height of 1.5 m were used. The unit packed towers 10a to 10d were filled with 0.57 L of calcium-type strongly acidic cation exchange resin (trade name: Monosphere 99Ca / 320, manufactured by Dow Chemical Company) as an adsorbent. The inside of each unit packed column was adjusted to 60 ° C.

[Example]
The circulation system was operated according to the operation steps shown in Table 1-1 below, and chromatographic separation was performed using a simulated moving bed system. The time taken for each sub-step, the amount of weakly adsorbable fraction (hereinafter referred to as “A fraction”) extracted in each sub-step, and the strongly adsorbable fraction (hereinafter referred to as “C fraction”). The amount of is shown in Table 1-2 below.
The conditions shown in Table 1-2 are conditions in which the operation steps shown in Table 1-1 are adopted, and the supply amount of the eluent is reduced as much as possible under the condition that the purity of fructose is 90% or higher in the C fraction. It is.
As shown in Table 1-1 below, when the cycle comprising the combination of step (a) and subsequent step (b) is repeated 4 times from 1 cycle to 4 cycles, the position of each supply valve and extraction valve is Return to the position of step (a) in the first cycle.
The numbers in the column of the valve opening / closing table in Table 1-1 correspond to FIG. For example, “1, 2, 3, 4” written in the column F means that the stock solution supply valves F1, F2, F3, F4 are opened, and numbers are not described. When (when blank), it means that the stock solution supply valve is closed. The same applies to the columns of the eluent supply valve D, the weakly adsorptive fraction extraction valve A, the strong adsorptive fraction extraction valve C, and the shutoff valve R.
In addition, “◯” in the column of the circulation pump in Table 1-1 means that the circulation pump is operated, and when the column is blank, it means that the circulation pump is not operated.

  In this chromatographic separation, fructose is a component to be purified (strongly adsorptive component), and glucose and oligosaccharide are combined to form a weakly adsorptive component.

The sugar composition of the A and C fractions was analyzed using a Tosoh HPLC 8020 series. The analysis conditions were as follows. The results are shown in Table 1-3 below.
<Analysis conditions>
Dual pump DP-8020
Differential Refraction System RI-8020
Autosampler AS-8020
Column: manufactured by Tosoh SCX-Ca 7.8 mmφ × 300 mm
Eluent: Deionized water Flow rate: 0.8 ml / min
Column temperature: 70 ° C
Sample injection volume: 10 μL

  As shown in Table 1-3 above, in the chromatographic separation of the examples, fructose can be recovered to a purity as high as 91.2% in the C fraction, and the sugar concentration in the C fraction is The concentration was as high as 40.8%. That is, it was found that the fructose can be recovered with high purity and high concentration in the C fraction by the chromatographic separation of the example.

  Subsequently, the recovery rate of the oligosaccharide recovered in the A fraction (the ratio of the oligosaccharide recovered in the A fraction out of the oligosaccharides in the stock solution, the same shall apply hereinafter), Recovery rate of recovered glucose (ratio of glucose recovered in fraction A out of glucose in stock solution, the same shall apply hereinafter) and recovery rate of fructose recovered in fraction C (in the stock solution) The ratio of fructose recovered in the C fraction of fructose, the same applies hereinafter) is shown in Table 1-4 below.

  As shown in Table 1-4, 92.7% of the fructose contained in the stock solution could be recovered in the C fraction by the chromatographic separation of the examples.

[Comparative Example 1]
In the examples, chromatographic separation by the simulated moving bed system was performed in the same manner as in the examples except that the circulation system was operated according to the operation steps shown in Table 2-1 and Table 2-2 below. This comparative example corresponds to the method described in Example 3 of JP-B-60-55162.
The conditions shown in Table 2-2 are the conditions in which the operation steps shown in Table 2-1 are adopted, the fructose purity is 90% or more in the C fraction, and the eluent supply is reduced as much as possible. is there.

  The sugar composition of the A fraction and the C fraction was analyzed in the same manner as the analysis in Example 1 above. The results are shown in Table 2-3 below.

  As shown in Table 2-3 above, in the chromatographic separation of Comparative Example 1, when fructose was recovered in the C fraction at a purity of 90.2%, the sugar concentration in the C fraction was 38.1%. It was. That is, it was found that the fructose in the C fraction had a low purity and the fructose concentration in the C fraction was greatly reduced as compared with the Examples.

  Next, the recovery rate of the oligosaccharide recovered in the A fraction, the recovery rate of the glucose recovered in the A fraction, and the recovery rate of the fructose recovered in the C fraction are shown in Table 2 below. -4.

As shown in Table 2-4, in the chromatographic separation of Comparative Example 1, 92.3% of fructose contained in the stock solution could be recovered in the C fraction. This recovery rate is slightly lower than in the examples.
Further, in Comparative Example 1, the fructose purity could not be increased to 90% or more unless more eluent was used than in the Examples (see “Dv / Fv” in Tables 1-2 and 2-2). ”Column).

[Comparative Example 2]
In Comparative Example 1, Comparative Example 1 except that the time taken for each sub-step and the amount of A fraction and C fraction extracted in each sub-step were changed as shown in Table 3-1 below. In the same manner as described above, chromatographic separation by a simulated moving bed method was performed.
The conditions shown in Table 3-1 are as follows: the stock solution total supply amount in sub-steps (ic) to (iiic) is the same as the stock solution total supply amount in sub-steps (i) to (iii) of the embodiment; The total amount of eluent supplied in steps (ic) to (iiic) is the same as the total amount of eluent supplied in sub-steps (i) to (iii) of the examples, and the purity of fructose in the C fraction is as much as possible. The conditions are set to increase.

  The sugar composition of the A fraction and the C fraction was analyzed in the same manner as the analysis in Example 1 above. The results are shown in Table 3-2 below.

  As shown in Table 3-2 above, in the chromatographic separation of Comparative Example 2, the purity of fructose in the C fraction could not be 90% or higher. Further, the sugar concentration in the C fraction was 39.5%. That is, it was found that the fructose purity in the C fraction was greatly reduced and the fructose concentration in the C fraction was also reduced as compared with the Examples.

  Next, the recovery rate of the oligosaccharide recovered in the A fraction, the recovery rate of the glucose recovered in the A fraction, and the recovery rate of the fructose recovered in the C fraction are shown in Table 3 below. -3.

  As shown in Table 3-3, in the chromatographic separation of Comparative Example 2, only 85.7% of the fructose contained in the stock solution could be recovered in the C fraction.

100 Circulating system 10a, 10b, 10c, 10d Unit packed tower Ab Adsorbent R1, R2, R3, R4 Shut-off valve 2a, 2b, 2c, 2d Weakly adsorbing fraction extraction line A1, A2, A3, A4 Weakly adsorbing Fraction extraction valve 4a, 4b, 4c, 4d Strong adsorption fraction extraction line C1, C2, C3, C4 Strong adsorption fraction extraction valve T1, T2, T3, T4 Check valve 1 Piping 3 Weak adsorption 5: Strongly adsorptive fraction merging pipe 6: Stock solution tank 7: Stock solution 8: Eluent tank 9: Eluent 11: Stock solution supply line 11a, 11b, 11c, 11d Stock solution supply branch line F1, F2, F3, F4 Stock solution supply valve 12 Eluent supply line 12a, 12b, 12c, 12d Eluent supply branch line D1, D2, D3, D4 Eluent supply valve P1 Circulation pump P2 Stock solution supply pump P3 Eluent supply pump U, V Leaf valve

Claims (6)

A chromatographic separation method for separating and purifying components in a stock solution by a simulated moving bed method using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly through a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
The following steps (a) and (b) are repeated in order:
(A) performing the following substeps (i) to (iv) in this order;
(I) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the strong adsorptive fraction from the strong adsorptive fraction extraction outlet C;
(Ii) a sub-step of supplying a stock solution from the stock solution supply port F and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(B) After the step (a) is completed, the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.   The chromatographic separation method according to claim 1, wherein a total amount of the strongly adsorptive fraction extracted from the outlet C in the step (a) is smaller than a total amount of the stock solution supplied from the supply port F. .   The chromatographic separation method according to claim 1 or 2, wherein the stock solution contains glucose and fructose, and the fructose is separated and purified in the strong adsorptive fraction.   The chromatographic separation method according to any one of claims 1 to 3, wherein the circulation system has at least four unit packed columns.   In the step (a), the ratio of the total supply amount of the eluent to the total supply amount of the stock solution satisfies the ratio [total supply amount of eluent] / [total supply amount of stock solution] <1.2 in volume ratio. The chromatographic separation method according to any one of claims 1 to 4. A chromatographic separation system that separates and purifies components in a stock solution by a simulated moving bed system using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
Repeat the following steps (a) and (b) in order, system:
(A) performing the following substeps (i) to (iv) in this order;
(I) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the strong adsorptive fraction from the strong adsorptive fraction extraction outlet C;
(Ii) a sub-step of supplying a stock solution from the stock solution supply port F and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(Iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(B) After the step (a) is completed, the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.

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